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Diagnosis

An accurate diagnosis is one of the most important aspects of a person’s medical care. Obtaining a precise diagnosis will help the doctor to

  • Estimate how the disease will progress
  • Determine the appropriate treatment.

The results of blood tests that accompany periodic medical examinations may indicate the need for further evaluation for myeloma. These include an elevated protein level, anemia and abnormalities in kidney function or calcium levels.

Diagnostic Criteria 

The diagnosis of myeloma depends on three principal findings

  • Increased numbers (more than 10 percent) of malignant plasma cells (myeloma cells) in a bone marrow biopsy sample or any atypical plasma cells indicating a plasmacytoma 
  • Unusually large amounts of monoclonal protein, referred to as “M spike.” Monoclonal proteins can be either intact monoclonal immunoglobulins or immunoglobulin light chains (Bence Jones proteins) found in the blood and/or urine.
  • Evidence of end-organ damage as defined by the CRAB criteria (see below). 

The International Myeloma Working Group (IMWG) recently updated the diagnostic criteria for myeloma to include biomarkers, in addition to the existing CRAB features.

Revised International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma

Both of the following criteria must be met:

  • Malignant plasma cells in the bone marrow ≥ 10% or presence of bony or extramedullary plasmacytoma, confirmed by biopsy
  • Any one or more of the following myeloma-defining events:
    • Evidence of end-organ damage that can be attributed to the disease (CRAB features)
      • Calcium elevation—serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
      • Renal failure—creatinine clearance < 40 mL per minute or serum creatinine > 177 μmol/L (> 2 mg/dL)
      • Anemia—hemoglobin concentration of > 2 g/dL below the lower limit of normal, or a hemoglobin concentration of < 10 g/dL
      • Bony lesions—one or more osteolytic lesions found on x-ray, CT or PET‑CT
    • Clonal plasma cells in the bone marrow ≥ 60%
    • Ratio of involved/uninvolved serum free light chain ratio ≥ 100
    • One or more focal lesions found on MRI studies (at least 5 mm in size)

Monoclonal Immunoglobulins (M Protein) and Light Chains (Bence Jones Protein)

In healthy individuals, plasma cells produce proteins called “polyclonal immunoglobulins.” These are a collection of antibodies that protect the body against all kinds of different invading viruses, bacteria or other infectious agents (antigens).

In myeloma, large amounts of a single antibody are noted as a “monoclonal immunoglobulin spike” or “monoclonal spike” (M spike), indicating that the protein came from cells that originally started as single, malignant cell. 

Monoclonal protein (M protein) levels can be measured in blood and/or urine samples, and these levels generally correlate with the extent of the myeloma.

A small number of patients with myeloma have either “oligosecretory disease,” in which the detectable level of monoclonal protein is low, or “nonsecretory disease,” in which no monoclonal protein can be detected. Some of these patients can be followed with a newer blood test that measures serum free light chains, which are a small fragment of the larger intact M protein.​

An intact immunoglobulin (Ig) molecule is composed of two larger pieces (heavy chains) and two smaller pieces (light chains) that are attached to each other. 

This whole (intact) immunoglobulin, made of the four chains, is usually too large to pass through the kidney. Thus, it is most often present in the blood but not in the urine. When the whole immunoglobulin is present in the urine, it is usually at a low level.

In some myeloma patients, the coordinated process of making and attaching light chains and heavy chains fails in the malignant plasma cells. Unattached, “free” light chains enter the blood and are excreted rapidly in the urine. The light chain is also called the “Bence Jones protein,” named for the doctor Henry Bence Jones who studied its characteristics. When excreted in large amounts, Bence Jones proteins (free light chains) can sometimes make the urine appear foamy and they can cause injury to the kidneys.

Each plasma cell produces one of five types of antibodies 

  • Immunoglobulin G (IgG) 
  • Immunoglobulin A (IgA)
  • Immunoglobulin M (IgM)
  • Immunoglobulin D (IgE)
  • Immunoglobulin E (IgD).

Myeloma cells produce many copies of its immunoglobulin. The most common type of myeloma is IgG, occurring in approximately 50 percent of patients. The next most common type is light chain myeloma in which no intact immunoglobulin is produced. 

Diagnostic Tests

Blood and Urine Tests. In some cases, myeloma isn't suspected until blood tests for other routine examinations indicate an elevated globulin level. This may lead to more tests, especially if you have no symptoms. If myeloma is suspected as a result, your doctor tests your blood again to help confirm a diagnosis. Your blood is sent to a lab for a complete blood count (CBC), which can reveal whether myeloma cells are affecting normal blood cell development, and a blood chemistry test, which can reveal abnormal levels of certain chemicals which may indicate an organ is not working properly. 

Your doctor also checks your blood for:

  • Calcium levels. High levels can mean that calcium has moved out of your bones and into your bloodstream, putting your kidney health at risk.

  • Protein levels. By measuring certain proteins, your doctor can estimate the size and growth rate of myeloma tumors.

  • Urea nitrogen and creatinine levels. These proteins are measured to test your kidney function.

Your doctor tests your urine (urinalysis) for Bence Jones protein, which can indicate the presence of myeloma. Bence Jones protein levels are measured to check kidney function and the extent of the disease.

Protein Electrophoresis Tests. Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are tests used to identify the presence of abnormal proteins, to identify the absence of normal proteins, and to determine increases and decreases of different groups of proteins in serum or urine. These tests are typically ordered to detect and identify excessive production of specific proteins (immunoglobulins). All five types of immunoglobulins (IgG, IgA, IgM, IgE, or IgD) are measured by these tests. If present, an excessive production of a monoclonal immunoglobulin may be shown on lab results as a spike on a graph (M protein or M spike). Most patients with untreated myeloma have a monoclonal immunoglobulin peak in serum, urine, or both.

These tests usually should be repeated at regular intervals to monitor the course of the patient’s myeloma and the effectiveness of treatment.

Serum Free Light Chain (SFLC) Assay. Serum free light chain testing provides complementary information to the two protein electrophoresis tests: SPEP and UPEP. The SFLC assay can detect abnormal levels of free light chains, which may be an indication of a plasma cell disorder. It can also detect changes in the ratio of kappa and lambda light chain production, which indicates an excess of abnormal plasma cells.

Bone Marrow Tests. Your doctor tests your bone marrow to look for increased numbers of myeloma cells. Bone marrow testing involves two steps usually done at the same time in a doctor's office or a hospital:

  • A bone marrow aspiration to remove a liquid marrow sample

  • A bone marrow biopsy to remove a small amount of bone filled with marrow.

Cytogenetic Analysis. Fluorescence in situ hybridization (FISH) is a type of laboratory test that uses special dyes to mark specific abnormal chromosomes in cells. Chromosomal abnormalities play a crucial role in identifying malignancies and determining the risk of relapse.

Imaging Tests. You may need to undergo an X-ray, a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan or a positron emission tomography (PET) scan. Your doctor looks for any evidence of bone damage, such as thinning, holes or fractures.

If you're diagnosed with myeloma, you may need to undergo more tests during or after treatment to see how the myeloma cells are responding to therapy.

In addition, doctors stage myeloma to help them decide on the best treatment plan.

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